Derivatives of 3.5-seco-4-norcholestane and use thereof

Abstract

The invention relates to compounds of formula (I): where X+Y=keto, or X=OH and Y=H, or X+Y=oxime or methyloxime, B=OH and C+D=H, or C+D=C1-C4 linear or branched alkyl, or C=H and D=C1-C4 linear or branched alkyl, or B+C=keto and D=methyl, hydroxyl, or methylamino, or B and C=H and D=methylamino, or B+C=oxime and D=methyl and R=C1-C10 linear or branched alkyl, the salts, esters, or salts of esters thereof as medicament, in particular as neuroprotectors, novel compounds of formula (I) and pharmaceutical compositions.

The invention claimed is: 
     
       1. A compound which is (a) a compound described by formula I 
       
         
           
           
               
               
           
         
       
       wherein
 (i) X represents together with Y and the carbon to which they are attached a keto function, or 
 (ii) X represents a hydroxyl group and Y a hydrogen, or 
 (iii) X and Y and the carbon to which they are attached together represent an oxime group (>C═NOH) or 
 (iv) X and Y and the carbon to which they are attached together represent a methyloxime group (>C═NOMe), and 
 
       wherein
 (1) B represents a hydroxyl group and C and D represent a hydrogen, or 
 (2) B represents a hydroxyl group and C and D represent linear or branched alkyls with 1 to 4 carbon atoms, or 
 (3) B represents a hydroxyl group and C represents a hydrogen and D a linear or branched alkyl with 1 to 4 carbon atoms, or 
 (4) B represents together with C and the carbon to which they are attached a keto function and D a methyl, hydroxyl or methylamine or 
 (5) B and C represent a hydrogen and D a methylamine, or 
 (6) B and C and the carbon to which they are attached together represent an oxime and D a methyl, and 
 
       wherein R represents a linear or branched alkyl with 1 to 10 carbon atoms;
 or which compound is (b) an addition salt of the compound of (a) with a pharmaceutically acceptable acid, or an ester of (a), or an addition salt of said ester with a pharmaceutically acceptable acid; 
 with the provisos that 
 if (i) applies, that (2), (3), (5) or (6) apply, 
 if (ii) applies, that (4), (5) or (6) apply, 
 if (iii) applies, that (2), (3), or (5) apply, and 
 if (iv) applies, that (1), (2), (3), (5) or (6) apply. 
 
     
     
       2. A compound according to  claim 1 , characterized in that in formula I, R represents the radical
   —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 .
 
 
     
     
       3. A compound according to  claim 1 , which is (a) a compound selected from the group consisting of
 3,5-seco-4-nor-cholestan-5-one oxime-3-methyl alcohol, and 
 3,5-seco-4-nor-cholestan-5-one oxime-3-dimethyl alcohol, or (b) an addition salt of (a) with a pharmaceutically acceptable acid or an ester of (a) or an addition salt of said ester with a pharmaceutically acceptable acid. 
 
     
     
       4. The compound of  claim 1  wherein condition (5) applies. 
     
     
       5. The compound of  claim 1  wherein
 if (i) applies, (2), (3) or (5) apply; 
 if (ii) applies, (4) or (5) apply; and 
 if (iv) applies, (2), (3) or (5) apply. 
 
     
     
       6. The compound of  claim 1  wherein (iii) applies. 
     
     
       7. A compound which is (a) a compound described by formula I 
       
         
           
           
               
               
           
         
       
       wherein
 X and Y and the carbon to which they are connected represent together an oxime, B and C represent a hydrogen and D a methyl amine, or 
 X represents together with Y and the carbon to which they are connected a keto function, B represents a hydroxyl radical, and C and D represent methyls, or 
 X and Y and the carbon to which they are connected together represent an oxime, B represents a hydroxyl, and C and D represent methyls, or 
 X and Y and the carbon to which they are connected together represent an oxime, B represents a hydroxyl, C represents a hydrogen and D represents a methyl, or 
 X and Y and the carbon to which they are connected together represent the methyl oxime group, B represents hydroxyl and C and D represent hydrogens, 
 or (b) an addition salt of the compound of (a) with a pharmaceutically acceptable acid, or an ester of (a), or an addition salt of the ester of (b) with a pharmaceutically acceptable acid 
 R represents a linear or branched alkyl with 1 to 10 carbon atoms. 
 
     
     
       8. A pharmaceutical composition characterized in that it comprises (I) as an active ingredient, a compound which is (a) the compound of formula I, 
       
         
           
           
               
               
           
         
       
       wherein
 (i) X represents together with Y and the carbon to which they are attached a keto function, or (ii) X represents a hydroxyl group and Y a hydrogen, or (iii) X and Y and the carbon to which they are attached together represent an oxime group (>C═NOH) or (iv) X and Y and the carbon to which they are attached together represent a methyloxime group (>C═NOMe), and 
 
       wherein
 (1) B represents a hydroxyl group and C and D represent a hydrogen, or (2) B represents a hydroxyl group and C and D represent linear or branched alkyls with 1 to 4 carbon atoms, or (3) B represents a hydroxyl group and C represents a hydrogen and D a linear or branched alkyl with 1 to 4 carbon atoms, or (4) B represents together with C and the carbon to which they are attached a keto function and D a methyl, hydroxyl or methylamine or (5) B and C represent a hydrogen and D a methylamine, or (6) B and C and the carbon to which they are attached together represent an oxime and D a methyl, 
 and wherein R represents a linear or branched alkyl with 1 to 10 carbon atoms, or which compound is (b) an addition salt of the compound of (a) with a pharmaceutically acceptable acid, or an ester of (a), or an addition salt of said ester with a pharmaceutically acceptable acid; 
 
       and (II) one or more inert, pharmaceutically acceptable additional ingredients, wherein all ingredients of said pharmaceutical composition are pharmaceutically acceptable. 
     
     
       9. The composition of  claim 8  wherein at least one inert, pharmaceutically acceptable ingredient is saline (sodium chloride). 
     
     
       10. The composition of  claim 8  wherein said saline is physiological saline. 
     
     
       11. The composition of  claim 8  wherein at least one inert, pharmaceutically acceptable ingredient is selected from the group consisting of methylcellulose, hydroxymethyl-cellulose, carboxymethylcellulse, cyclodextrins, polysorbate 80, mannitol, gelatin, lactose, vegetable or animal oils, and acacia. 
     
     
       12. The composition of  claim 8  which is the form of a gel, tablet, suppository or capsule. 
     
     
       13. The composition of  claim 8  which is in the form of an oily suspension. 
     
     
       14. The composition of  claim 8  which is in the form of an injectable suspension. 
     
     
       15. The composition of  claim 8  in unit dosage form. 
     
     
       16. A method for providing neuroprotection of neurons which comprises exposing neurons to a neuron-protective amount of a compound that is capable of protecting neurons, which compound is (a) a compound described by formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 (i) X represents together with Y and the carbon to which they are attached a keto function, or (ii) X represents a hydroxyl group and Y a hydrogen, or (iii) X and Y and the carbon to which they are attached together represent an oxime group (>C═NOH) or (iv) X and Y and the carbon to which they are attached together represent a methyloxime group (>C═NOMe), and 
 
       wherein
 (1) B represents a hydroxyl group and C and D represent a hydrogen, or (2) B represents a hydroxyl group and C and D represent linear or branched alkyls with 1 to 4 carbon atoms, or (3) B represents a hydroxyl group and C represents a hydrogen and D a linear or branched alkyl with 1 to 4 carbon atoms, or (4) B represents together with C and the carbon to which they are attached a keto function and D a methyl, hydroxyl or methylamine or (5) B and C represent a hydrogen and D a methylamine, or (6) B and C and the carbon to which they are attached together represent an oxime and D a methyl, 
 and wherein R represents a linear or branched alkyl with 1 to 10 carbon atoms, 
 
       or which compound is (b) an addition salt of the compound of (a) with a pharmaceutically acceptable acid, or an ester of (a), or an addition salt of said ester with a pharmaceutically acceptable acid. 
     
     
       17. The method according to  claim 16 , characterized in that the compound of formula I is 3,5-seco-4-nor-cholestan-5-one oxime-3-ol, or one of its addition salts with pharmaceutically acceptable acids or one of its esters or one of the addition salts with pharmaceutically acceptable acids of said esters. 
     
     
       18. The method of  claim 16  wherein the neurons are motoneurons, and the motoneurons are protected from degeneration or death. 
     
     
       19. The method of  claim 18  wherein the protection occurs in a subject suffering from a neurodegenerative disease or pathology. 
     
     
       20. The method of  claim 19  wherein the disease or pathology is a spinal muscular atrophy. 
     
     
       21. The method of  claim 19  wherein the disease or pathology is an infantile spinal muscular atrophy. 
     
     
       22. The method of  claim 19  wherein the disease or pathology is amyotrophic lateral sclerosis. 
     
     
       23. The method of  claim 19  wherein the disease or pathology is multiple sclerosis. 
     
     
       24. The method of  claim 16  wherein
 if (i) applies, (1), (2) or (4) apply; and 
 if (ii) or (iv) applies, (1) applies. 
 
     
     
       25. The method of  claim 16  wherein (iii) applies.